Papillomavirus transcription and DNA replication are regulated, at least in part, by the products of the viral E1 and E2 open reading frames. Structural and functional analyses of the E1 and E2 proteins have been carried out to provide some insight into the mechanisms by which these proteins regulate the viral life cycle. The E1 and E2 proteins form a complex that binds co-operatively to the viral origin of replication. It has been shown that a region of the E1 protein between residues 162 and 378 is important for origin- specific DNA binding. A large C-terminal domain of the E1 protein is required for co-operative DNA binding and for interaction with the E2 protein. The N-terminal 200 amino acids of the E2 protein forms a multifunctional domain important for transcription and replication. In an attempt to separate these properties and to understand the mechanisms by which the E2 proteins function, an extensive mutational analysis of this domain has been carried out. These studies have identified E2 residues important for transcriptional regulation and DNA replication. A short peptide sequence that is responsible for nuclear targeting of the E2 proteins has been identified. This signal is contained within the region of the E2 DNA binding domain that forms a recognition helix for sequence-specific DNA binding.